Lysophosphatidic acids (LPAs) are lysophospholipid mediators that can evoke a variety of responses when applied to living mammalian cells. These include calcium mobilization, changes in the cytoskeleton that may lead to increased migration, increased cell survival, resistance to apoptosis and mitogenesis. LPA is also believed to promote platelet aggregation in a number of mammalian species including humans. Further, LPA is a pro-angiogenic factor. LPA signals through a set of at least three G protein-coupled receptors, named LPA1, LPA2 and LPA3 (formerly EDG2, EDG4 and EDG7). Other receptors for LPA, including the G protein-coupled receptors GPR23 and GPR92 and a nuclear hormone receptor (PPAR-γ) have been suggested.
LPA is an intermediate that is present during phospholipid biosynthesis in all cells. It is made via a common de novo phospholipid biosynthetic pathway. Extracellular (plasma) LPA is derived mainly by the action of the plasma phosphodiesterase, autotaxin (ENPP-2), on lysophosphatidylcholine (LPC). LPA levels in human plasma are reported to be in the range of about 200-600 nanomolar (nM). LPA in serum is derived, directly and indirectly, from activated platelets. Serum LPA concentrations are in the range of about 2-6 micromolar (μM). Extracellular LPA accumulation is characteristic of the ascitic fluid often associated with human ovarian cancer. LPA is believed to be a pro-mitogenic stimulus for the ovarian cancer cells. LPA concentrations in these malignant ascites has been reported to be in the range of about 2-50 μM.
LPA has been suggested to have a role in preventing the progression of neoplastic diseases. However, the lack of suitable LPA receptor antagonist molecules has made this difficult to prove. LPA is angiogenic in a chicken chorioallantoic membrane model, which suggests a role of LPA signaling in angiogenic processes such tumor development. Mice wherein the LPA, receptor gene is deleted do not develop neuropathic pain normally, which suggests a role for this receptor type in development of neuropathic pain.
Currently, there is a need for novel, potent, and selective compounds and methods for preventing the progression of cancers. There is a longstanding need to identify LPA receptor antagonists that can modulate the activity of one or more LPA receptors. The present invention satisfies these needs.